Discovery that genes determine the severity of Multiple Sclerosis

Researchers at the Wellcome Trust Centre for Human Genetics (WTCHG) at the University of Oxford have made a major new insight into the interaction of genes involved in Multiple Sclerosis (MS). They have discovered that the specific combination of two different versions of the same gene, one coming from each parent, determine the outcome for patients. It has long been known that MS is extremely variable, but this study is the first insight into why this is the case.

The research team at WTCHG, led by Professor George Ebers, undertook four independent but conceptually interlinked studies. The first study compared forms (alleles) of a specific gene, HLA-DRB1, in 160 MS patients with benign and malignant disease, representing the opposite extremes of long-term disease outcome. The second study was of benign and malignant MS sufferers in Sardinia, an island with an unusually high rate of the disease. The third study looked at siblings who both had MS, but with different versions of HLA-DRB1. The results of all three studies indicated that one allele of DRB1 was protective against the severe form of the disease. A fourth study, of a distinct but close relative of this allele, showed the same effect.

This research may have localised the molecular basis of MS to the short DNA stretch shared by the two protective alleles of the gene. The group had previously shown that one of these alleles is among several which are partially protective for risk. Now it appears that among those who have the allele from a parent and still get MS, the severe form of the disease is minimised. It seems to operate by somehow blocking the effects of the main MS susceptibility allele HLA-DRB1*1501 which would be inherited from the other parent.

Professor Ebers said: 'The analysis of these studies has yielded the first clear insight into the mechanism of disease variability and we are very excited about the potential practical applications of our findings.'

There are few diseases in which the outcome varies between such extremes as MS. For some, the disease is mild and causes intermittent symptoms of a minor nature. But for others it can be fatal within 12 months. Evidence for genetic factors in disease outcome comes from sibling research, particularly studies on identical twins. The results of the studies undertaken by Prof Ebers' team at the WTCHG may have far-reaching consequences for the future of MS research and treatment. There may some practical value in screening families to determine whether they have protective alleles and if MS is present there may be potential for practical prognostication. At present this would be only relative and apply to a minority of patients. However there is reason to think the gene-gene interaction identified will be part of a more general phenomenon and that more such observations will serve to refine information which can usefully be passed on to those with the disease. The results will also guide future research, as scientists can now focus on studying how the 01 allele interacts with other genes to reduce severity, suggesting new therapeutic strategies.